Sunday, September 22, 2013

Should tolvaptan be used routinely for hyponatremia in patients with heart failure? Na.

One can hardly open a medical publication without seeing an advertisement for Otsuka's tolvaptan (Samsca®), an oral vasopressin antagonist approved for the management of hyponatremia in the setting of heart failure. Despite only minimal improvements in clinical trials and new warnings issued by the US Food & Drug Administration (FDA), the use of tolvaptan remains a topic of interest.

Hyponatremia is common among hospitalized patients and is associated with poor prognosis among those with heart failure [1]. What is less clear, however, is whether this relationship is a result of cause-and-effect or merely correlation. The latter is worth investigating, as this has been observed with other surrogate markers that were once considered potential therapeutic targets, with hemoglobin being one of the most recent to be called into question [2].

To date, the available evidence suggests that, while serum sodium concentrations can be improved with vasopressin antagonist therapy, these changes do not appear to confer meaningful differences in clinical outcomes. In SALT, a trial evaluating the use of tolvaptan in patients with hyponatremia (a third of whom had heart failure), patients randomized to tolvaptan experienced improvements in urine output and serum sodium concentrations, but this only persisted while patients were on therapy; in less than a week after discontinuing tolvaptan, serum sodium concentrations returned to baseline [3]. In EVEREST, a trial specifically enrolling patients with acute decompensated heart failure (irrespective of serum sodium concentrations), those randomized to tolvaptan experienced greater reductions in body weight (although less than a kg difference versus placebo) and improvements in some but not all heart failure signs and symptoms [4]. Tolvaptan failed to impart any clinically meaningful differences in mortality, hospitalizations, worsening heart failure, or quality of life [5]. Serum sodium concentrations improved initially but these differences dissipated with time.

In other words, tolvaptan and other vasopressin antagonists appear to have no appreciable effect on the underlying pathophysiology of heart failure. While serum sodium concentrations can be improved, recurrence of hyponatremia should be expected following cessation of therapy if underlying causes (e.g., reduced renal perfusion, hypervolemia, etc.) are not addressed. Coupled with emerging evidence of liver injury that eventually prompted FDA to limit its use to less than 30 days (and avoid it altogether in patients with evidence of liver impairment), tolvaptan has only limited utility in patients with heart failure.

There are a couple of scenarios where a short course of tolvaptan may be considered:
  • Patients with symptomatic hyponatremia at any serum sodium concentration; or,
  • As a temporizing measure (i.e., up to 5 days or so) to stabilize critically low serum sodium concentrations (< 125 mEq/L, to prevent patients from becoming symptomatic) while underlying causes are corrected, i.e., discontinuation of potentially offending drugs (select antipsychotics and antidepressants, thiazide diuretics), optimization of standard heart failure therapies, addition of vasodilators or inotropes to improve renal perfusion, or aggressive diuresis to correct hypervolemia.
That being said, there is evidence that suggests small boluses of hypertonic saline can improve hyponatremia in these scenarios without worsening fluid balance [6].

In summary, routine use of tolvaptan should be avoided, as it both fails to improve long-term clinical outcomes and represents an incredibly expensive strategy for improving symptoms and/or treating a surrogate marker that has yet to be associated with improved clinical endpoints. Although the price of tolvaptan has likely come down since its introduction to the market, at one time its use represented spending about $50 for each mEq/L increase in serum sodium concentration per day, and about $3 for each additional mL of urine output per day.

Note: I borrowed the title for this entry from an old Chemistry Cat meme, so let me end by giving credit (or blame?) to whomever it is due.

  1. Adams KF Jr, Fonarow GC, Horton DP, et al; ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005 Feb;149(2):209-16.
  2. Swedberg K, Young JB, van Veldhuisen DJ, et al; for the RED-HF Investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013 Mar 28;368(13):1210-9.
  3. Schrier RW, Gross P, Orlandi C, et al; for the SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006 Nov 16;355(20):2099-112.
  4. Gheorghiade M, Konstam MA, Orlandi C, et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. 2007 Mar 28;297(12):1332-43.
  5. Konstam MA, Gheorghiade M, Orlandi C, et al; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007 Mar 28;297(12):1319-31.
  6. Licata G, Di Pasquale P, Paterna S, et al. Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as bolus in refractory congestive heart failure: long-term effects. Am Heart J. 2003 Mar;145(3):459-66.

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